Tyrosine kinase inhibitors

Abstract

The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.

What is claimed is:  
     
       1. A compound of Formula I                    
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein 
       Y is S;  
       Q is O or absent;  
       R 1  is:  
       1) O r (C 1 -C 6 )perfluoroalkyl,  
       2) OH,  
       3) CN,  
       4) halogen,  
       5) (C═O) r O s (C 1 -C 10 )alkyl,  
       6) (C═O) r O s (C 2 -C 8 )cycloalkyl,  
       7) (C═O) r O s (C 2 -C 10 )alkenyl,  
       8) (C═O) r O s (C 2 -C 10 )alkynyl,  
       9) (C═O) r O s aryl,  
       10) (C═O) r O s heterocyclyl, or  
       11) NR a R b ,  
       wherein r and s are independently 0 or 1, and said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ;  
       R 2  is R 1  or H;  
       R 4  is H or (C 1 -C 6 )alkyl;  
       R 5  is:  
       1) H,  
       2) SO 2 R c ,  
       3) (C═O) r R c , wherein r is 0 or 1, or  
       4) CO 2 R c ;  
       R 7  is:  
       1) O r (C═O) s NR a R b ,  
       2) (C═O) r O s aryl,  
       3) (C═O) r O s -heterocyclyl,  
       4) halogen,  
       5) OH,  
       6) oxo,  
       7) O(C 1 -C 3 )perfluoroalkyl,  
       8) (C 1 -C 3 )perfluoroalkyl,  
       9) (C═O) r O s (C 1 -C 10 )alkyl,  
       10) CHO,  
       11) C 2 H,  
       12) CN, or  
       13) (C 3 -C 8 )cycloalkyl,  
       wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one or more substituents selected from R d ;  
       R a  and R b  are independently:  
       1) H,  
       2) (C═O) r ( C 1 -C 10 )alkyl,  
       3) (C═O) r (C 3 -C 6 )cycloalkyl,  
       4) S(O) 2 R c ,  
       5) (C═O) r heterocyclyl,  
       6) (C═O) r aryl, or  
       7) CO 2 R c ,  
       wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one or more substituents selected from R d , or  
       R a  and R b  are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R d ;  
       R c  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl;  
       R d  is selected from:  
       1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2  and S(O) 2 R c ,  
       2) O r (C 1 -C 3 )perfluoroalkyl,  
       3) (C 0 -C 6 )alkylene-S(O) m R c , wherein m is 0, 1, or 2,  
       4) oxo,  
       5) OH,  
       6) halo,  
       7) CN,  
       8) (C 3 -C 6 )cycloalkyl, optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2 , and S(O) 2 R c ,  
       9) (C 0 -C 6 )alkylene-aryl), optionally substituted with up to three substituents selected from R e ,  
       10) (C 0 -C 6 )alkylene-heterocyclyl, optionally substituted with up to three substituents selected from R e ,  
       11) (C 0 -C 6 )alkylene-N(R e ) 2 ,  
       12) C(O)R c ,  
       13) CO 2 R c ,  
       14) C(O)H, and  
       15) CO 2 H; and  
       R e  is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl or S(O) 2 R c ;  
       and as used herein, the term “heterocycle” or “heterocyclyl” is a 5- to 10-membered aromatic or nonaromatic, monocyclic or bicyclic, heterocycle, containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S. 
     
     
       2. The compound of  claim 1 , wherein Y is S and Q is absent. 
     
     
       3. The compound of  claim 2 , wherein 
       R 1  is:  
       1) O r (C 1 -C 6 )perfluoroalkyl,  
       2) OH,  
       3) CN,  
       4) halogen,  
       5) (C═O) r O s (C 1 -C 6 )alkyl,  
       6) (C═O) r O s (C 2 -C 6 )cycloalkyl,  
       7) (C═O) r O s (C 2 -C 6 )alkenyl,  
       8) (C═O) r O s (C 2 -C 6 )alkynyl,  
       9) (C═O) r O s aryl,  
       10) (C═O) r O s heterocyclyl, or  
       11) NR a R b ,  
       wherein r and s are independently 0 or 1, and said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and heterocyclyl is optionally substituted, with one, two or three substituents selected from R 7 ;  
       R 7  is:  
       1) O r (C═O) s NR a R b ,  
       2) (C═O) r O s aryl,  
       3) (C═O) r O s -heterocyclyl,  
       4) halogen,  
       5) OH,  
       6) oxo,  
       7) O(C 1 -C 3 )perfluoroalkyl,  
       8) (C 1 -C 3 )perfluoroalkyl,  
       9) (C═O) r O s (C 1 C 6 )alkyl,  
       10) CHO,  
       11) C 2 H,  
       12) CN, or  
       13) (C 3 -C 6 )cycloalkyl,  
       wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one, two or three substituents selected from R d ;  
       R a  and R b  are independently:  
       1) H,  
       2) (C═O) r (C 1 -C 6 )alkyl,  
       3) (C═O) r (C 3 -C 6 )cycloalkyl,  
       4) S(O) 2 R c ,  
       5) (C═O) r heterocyclyl,  
       6) (C═O) r aryl, or  
       7) CO 2 R c ,  
       wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one, two or three substituents selected from R d , or  
       R a  and R b  are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R d ;  
       R c  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or aryl; and  
       R d  is selected from:  
       1) (C═O) r O s (C 1 -C 6 )alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2  and S(O) 2 R c ,  
       2) O r (C 1 -C 3 )perfluoroalkyl,  
       3) (C 0 -C 6 )alkylene-S(O) m R c , wherein m is 0, 1, or 2,  
       4) oxo,  
       5) OH,  
       6) halo,  
       7) CN,  
       8) (C 3 -C 6 )cycloalkyl, optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2 , and S(O) 2 R c ,  
       9) (C 0 -C 6 )alkylene-aryl, optionally substituted with up to three substituents selected from R e ,  
       10) (C 0 -C 6 )alkylene-heterocyclyl, optionally substituted with up to three substituents selected from R e ,  
       11) (C 0 -C 6 )alkylene-N(R e ) 2 ,  
       12) C(O)R c ,  
       13) CO 2 R c ,  
       14) C(O)H, and  
       15) CO 2 H.  
     
     
       4. The compound of  claim 2 , wherein 
       R 1  is (C 1 -C 10 )alkylene-NR a R b , optionally substituted with one or two substituents selected from R 7 ;  
       R 2  is H, CN, halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyloxy;  
       R 5  is H, (C 1 -C 6 )alkyl, CO 2 (C 1 -C 6 )alkyl, or,CO(C 1 -C 6 )alkyl;  
       R 7  is:  
       1) O r (C═O) s NR a R b ,  
       2) (C═O) r O s aryl,  
       3) (C═O) r O s -heterocyclyl,  
       4) halogen,  
       5) OH,  
       6) oxo,  
       7) O(C 1 -C 3 )perfluoroalkyl,  
       8) (C 1 -C 3 )perfluoroalkyl,  
       9) (C═O) r O s (C 1 -C 6 )alkyl,  
       10) CHO,  
       11) CO 2 H,  
       12) CN, or  
       13) (C 3 -C 6 )cycloalkyl,  
       wherein r and s are independently 0 or 1 , and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one or two substituents selected from R d ;  
       R a  and R b  are independently selected from:  
       1) H,  
       2) (C═O) r (C 1 -C 6 )alkyl,  
       3) (C═O) r (C 3 -C 6 )cycloalkyl,  
       4) S(O) 2 R c ,  
       5) (C═O) r heterocyclyl,  
       6) (C═O) r aryl, and  
       7) CO 2 R c ,  
       wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one to three substituents selected from R d , or  
       R a  and R b  are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one additional heteroatom selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or two substituents selected from R d ;  
       R c  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or aryl; and  
       R d  is selected from:  
       1) (C═O) r O s (C 1 -C 6 )alkyl, wherein r and s are independently 0 or 1,optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2  and S(O) 2 R c ,  
       2) O r (C 1 -C 3 )perfluoroalkyl,  
       3) (C 0 -C 6 )alkylene-S(O) m R c , wherein m is 0, 1, or 2,  
       4) oxo,  
       5) OH,  
       6) halo,  
       7) CN,  
       8) (C 3 -C 6 )cycloalkyl, optionally substituted with up to three substituents selected from OH, (C 1 -C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2 , and S(O) 2 R c ,  
       9) (C 0 -C 6 )alkylene-aryl, optionally substituted with one or two substituents selected. from R e ,  
       10) (C 0 -C 6 )alkylene-heterocyclyl, optionally substituted with one or two substituents selected from R e ,  
       11) (C 0 -C 6 )alkylene-N(R e ) 2 ,  
       12) C(O)R c ,  
       13) C 2 R c ,  
       14) C(O)H, and  
       15) CO 2 H.  
     
     
       5. A compound selected from: 
       2-[4-(4-methyl-5-oxo-[1,4]diazepan-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile;  
       2-[4-(4-acetyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile;  
       2-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile;  
       2-[4-(1,1-dioxo-thiomorpholin-4-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile;  
       2-{4-[4-(2-hydroxy-ethanoyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-thiazole-5-carbonitrile;  
       N-{1-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-pyrrolidin-3-yl}-methanesulfonamide;  
       4-({2-[(5-cyano-1,3-thiazol -2-yl)amino]-4-pyridinyl}methyl)-N,N-dimethyl-1-piperazinecarboxamide;  
       2-[(4-{[(5-oxo-3-pyrrolidinyl)amino]methyl}-2-pyridinyl)amino]-1,3-thiazole-5-carbonitrile;  
       4-({2-[(5-cyano-1,3-thiazol-2-yl)amino]-4-pyridinyl}methyl)-1-piperazinecarboxamide;  
       2-[(4-{[3-(methylsulfonyl)-1-pyrrolidinyl]methyl}-2-pyridinyl)amino]-1,3-thiazole-5-carbonitrile;  
       2-[4-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile;  
       2-(4-morpholin-4-ylmethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile;  
       2-(4-{[(piperidin-4-ylmethyl)-amino]-methyl}-pyridin-2-ylamino)-thiazole-5-carbonitrile; and  
       2-(4-piperazin-1-ylmethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.  
     
     
       6. A pharmaceutical composition which is comprised of a compound in accordance with  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       7. A pharmaceutical composition made by combining the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       8. A process for making a pharmaceutical composition which comprises combining a compound of  claim 1  with a pharmaceutically acceptable carrier.